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CD46-Induced Immunomodulatory CD4⁺ T Cells Express the Adhesion Molecule and Chemokine Receptor Pattern of Intestinal T Cells¹

Shannon K. Alford^*,||, Gregory D. Longmore^*,,¶, William F. Stenson^*, and Claudia Kemper^2,*,

^* Department of Internal Medicine, Division of Hematology, Division of Gastroenterology, Division of Rheumatology, ^¶ Department of Cell Biology, and ^|| Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110

Tissue homing of activated T cells is typically mediated through their specific integrin and chemokine receptor repertoire. Activation of human primary CD4⁺ T cells in the presence of CD46 cross-linking induces the development of a distinct immunomodulatory T cell population characterized by high IL-10/granzyme B production. How these regulatory T cells (Tregs) migrate/home to specific tissue sites is not understood. In this study, we determined the adhesion protein and chemokine receptor expression pattern on human CD3/CD46-activated peripheral blood CD4⁺ T cells. CD3/CD46-activated, but not CD3/CD28-activated, T cells up-regulate the integrin ₄β₇. The interaction of ₄β₇ with its ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) mediates homing or retention of T cells to the intestine. CD3/CD46-activated Tregs adhere to/roll on MAdCAM-1-expressing HeLa cells, similar to T cells isolated from the human lamina propria (LP). This interaction is inhibited by silencing MAdCAM-1 expression in HeLa cells or by the addition of blocking Abs to β₇. CD46 activation of T cells also induced the expression of the surface-bound cytokine LIGHT and the chemokine receptor CCR9, both marker constitutively expressed by gut LP-resident T cells. In addition, we found that 10% of the CD4⁺ T lymphocytes isolated from the LP of patients undergoing bariatric surgery contain T cells that spontaneously secrete a cytokine pattern consistent with that from CD46-activated T cells. These data suggest that CD46-induced Tregs might play a role in intestinal immune homeostasis where they could dampen unwanted effector T cell responses through local IL-10/granzyme B production.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the Sandler Program for Asthma Research and National Institutes of Health Grants U19 AI070489, R01 DK33165, and R01 DK55753.

² Address correspondence and reprint requests to Dr. Claudia Kemper at the current address, Medical Research Council Centre for Transplantation, King’s College London, 5th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, U.K. E-mail address: claudia.kemper{at}kcl.ac.uk

³ Abbreviations used in this paper: Treg, T regulatory cell; IBD, inflammatory bowel disease; LP, lamina propria; MAdCAM-1, mucosal addressin cell adhesion molecule 1; LPL, LP-resident lymphocyte; siRNA, small interfering RNA; DIC, differential interference contrast; RA, retinoic acid; DC, dendritic cell; sCD40L, soluble CD40 ligand.

⁴ The online version of this article contains supplemental material.